ABSTRACT Methamphetamine (METH) addiction and Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) represent major chronic health problems in the US and abroad. Magnetic Resonance Imaging (MRI) studies have consistently shown structural and functional abnormalities in the dopaminergic system, while Positron Emission Tomography (PET) studies reported dopamine transporter (DAT) density reductions in patients with HIV and METH. Advances in treatment of METH toxicity and HAND have been made by administering brain derived neurotrophic factor (BDNF) directly to the CNS, or by using drugs that can increase BDNF indirectly. BDNF promotes neuronal survival, plasticity and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. The goal of this effort is to produce nontoxic, BDNF-nanoparticles (NPs), and test the hypothesis that (a) these NPs bypass the BBB intranasally, (b) target dopaminergic brain regions, and (c) prevent or reverse neurotoxic effects of METH and HIV transactivator of transcription (tat) protein in a mouse model relevant to HAND (the GT-tg bi-genic mouse induced with doxycycline to overexpress tat protein). To accomplish these goals we will design a three-part nanoparticle (<50 nanometers). A nanocarrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting molecules into cells. The second component will be a BDNF protein drug. The third part will be a targeting DAT ligand (e.g., GBR12935). BDNF and DAT ligands will be attached to clathrin via polyethylene glycol (PEG) molecules. A series of studies will ascertain specificity and functionality of the NP in vivo. We plan to demonstrate the feasibility of this novel nanotechnology to treat METH and tat-induced neurotoxicity. If this research project is successful it will provide new noninvasive nanotechnology tools for treatment of neurotoxicity in METH addiction and HAND. The new nanotechnology may be able to enhance neuronal survival and plasticity and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular NP may also provide a major new tool for research of molecular abnormalities in HAND and drug addiction. This novel nanotechnology may serve as the basis for a next generation drug- delivery system that can specifically target relevant brain systems and release drugs on demand, and may also have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.